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HBV combination therapy newer advances
1. Carrie R. Wong. et al.
(J Clin Gastroenterol. Nov-2011;45:900–905)
PRESENTED BY
VINEET MISHRA
2. Introduction
Oral nucleos(t)ides are the most commonly used HBV antiviral
agents for treatment of chronic hepatitis B
Nucleos(t)ides for HBV therapy belong to three classes
L-nucleosides -(lamivudine, telbivudine, and emtricitabine),
Deoxyguanosine analogues (entecavir)
Acyclic nucleoside phosphonates (adefovir and tenofovir)
3. RESPONSE RATE IN HBeAg POSITIVE PATIENTS
EASL GUIDELINE (JOURNAL OF HEPATOLOGY 2009 )
6. Ongoing replication during antiviral
therapy can lead to the emergence
of resistance
Wild type HBV
Genetically diverse
HBV population
HBV variants
Resistant HBV
Nucleos(t)ide
analogue therapy
Continued
therapy
Compensatory mutations
may occur which restore
viral fitness
With ongoing
replication
Reduced population may
include resistant HBV
Selective pressure favours
resistant HBVa
Ghany M & Liang TJ. Gastroenterology 2007;132:1574-85.
7. Background
Most common causes of treatment failure to oral
nucleos(t)ides are partial response (PR) and antiviral drug
resistance (AVR)
Rescue therapy in these settings often requires combination
therapy with a nucleoside and nucleotide
Although the literature on clinical outcomes of combination
treatment is sparse
Recommendations for combination therapy from earlier
studies have either been controversial or limited by small
sample size
8. Background
In fact, current guidelines discouraged the use of sequential
monotherapy favoring combination therapy over sequential
monotherapy, especially in the case of antiviral resistance
So, this study was retrospectively planned to find out efficacy
and tolerability of various antiviral combination treatment
regimens among patients with prior treatment failure for
Chronic Hepatitis B
9. AIMS AND OBJECTIVES
The primary objective was to determine the rate of complete
viral suppression (CVS) by using combination therapy
Secondary objective was to compare CVS(complete viral
suppression) among different combination treatment regimens
and indications
10. MATERIALS AND METHODS
A retrospective cohort of 109 consecutive patients with
Chronic Hep B who were treated with combination HBV
antiviral therapy at 3 gastroenterology and liver clinics in
Northern California were analyzed
All patients began their current combination regimens
between April 2004 and August 2009 and were treated for at
least 6 months at the time of data analysis
ETV+TDF (n=41)
ADV+ETV (n=22)
TDF+emtricitabine (n=19)
LAM+ADV (n=13)
LAM+TDF (n=10)
LdT+TDF (n=2)
ADV+LdT (n=2)
11. MATERIALS AND METHODS
The AVR (antiviral drug resistance ) was defined as
AVR indication for combination therapy was defined as confirmed
resistance based on genetic test results (n=25) or the presence of
virologic breakthrough, defined as a documented rise in serum HBV
DNA by ≥ 1 log10 IU/ mL from nadir during continuation of initial
therapy (n=4)
The PR(partial response) was defined as
detectable serum HBV DNA levels during prior therapy without the
development of AVR
Complete Viral Suppression was defined
as having undetectable serum HBV-DNA as reported by local
laboratories (<29 to 100 IU/mL)
12. Standard doses of oral agents for treatment of
Chronic Hepatitis B were used:
.
LAM 100 mg daily
ADV 10 mg daily
LdT 600 mg daily
ETV 0.5 or 1.0 mg daily
TDF 300 mg daily
TRUVADA (TDF 300mg+FTC 200mg daily)
Indications for combination therapy were grouped into 3 categories
AVR (antiviral drug resistance ) to prior treatment (n=29),
PR (partial response) to prior therapy (n=60), and
others (n=20, with 13 due to patients request for more potent
regimens, 7 due to side effects)
Some of the patients in the PR group had prior LAM therapy with
the development of resistance, but had PR to their second drug
that led to the addition of an additional agent
13.
14.
15. RESULTS
Baseline Characteristics
Nearly all patients were Asian (99%), with the majority being
Vietnamese and/or Chinese (82%)
The majority of patients had HBV genotype B (53%) or C (46%)
Detectable HBeAg in 60%
Of the 109 patients, 17 had cirrhosis
16. Treatment Outcomes
The median treatment duration on the current combination
therapy was 21 months (range, 6 to 50 mo)
The majority of patients achieved Complete Viral
Suppression by 6 months (77%) and continued to achieve or
maintain Complete Viral Suppression at 12, 18, and 24
months
The median time to achieve Complete Viral Suppression was
6 months (range, 1 to 37 mo)
Only 11 patients did not have Complete Viral Suppression by
the end of treatment or by their most recent follow-up
17. Treatment Outcomes…..
Patients who did not achieve Complete Viral Suppression were
on the following combinations: LAM+ADV (n=4), ETV+TDF
(n=4), ADV+ETV (n=2), and TDF+FTC (n=1).
Only 4 of these patients remained on their current combination
therapies, whereas the other 7 were switched to another
regimen of antiviral therapy
No patient had HBeAg loss or seroconversion with combination
therapy
Over half of patients achieved normalization of ALT levels while
receiving combination therapy
19. Comparison of Complete Viral
Suppression by Combination Treatment
Regimens
Two different groups of TDF-based combinations, that is, TDF+ETV
and TDF+LAM or FTC or LdT, had a similar number of patients with
detectable serum HBV DNA at baseline (83% and 81%, respectively)
The proportion of patients with Complete Viral Suppression at
6, 12, and 24 months (80%, 80%, 89% in TDF+ETV group and
76%, 96%, 100% in other group )
20. Comparison of Complete Viral
Suppression by Combination
Treatment Regimens
The comparison of Complete Viral Suppression rates among various
ETV based combination treatments revealed insignificant differences
The TDF+ETV group had a faster rate of Complete Viral Suppression
than the TDF+LAM or FTC or LdT group: median 5 versus 6
months, but this difference was not statistically significant
21. Comparison of Complete Viral
Suppression by Indications for
Combination Therapy
Analysis of patients by AVR and PR indications revealed no
significant differences in Complete Viral Suppression rates
between the 2 groups
Both groups had similar proportions of patients with Complete
Viral Suppression at 6 months (72% vs. 74%)
22. Tolerability
Side effects during combination treatment were reported
in 11 patients
Possible causal relationships with treatment were present in
4 of these patients.
Decrease in GFR occured in 5 patients who were on
LAM+ADV (n=2), ETV+TDF (n=2), and TDF+FTC (n=1),
but none had GFR <65 mL/min or 20% lower than their
pretreatment levels
23.
24. Strength of the study
Evaluated clinical outcomes in a real-life clinical setting
Treatment outcomes were also observe in patients who
received newer agents such as ETV and TDF
Due to lack of data on combination oral drugs therapy, this
study will provide feasibility of further prospective study
regarding combination in case of drugs resistance or
partial response
25. Limitations of study
Retrospective design and
No standardized monitoring for nonadherence
Lack of routine viral resistance surveillance
Baseline laboratory data were not available for all patients and
was considered baseline if available within 3 months before the
initiation of combination therapy
26. Limitations of study
Didn’t provide the baseline characteristic detail of different
groups of combination therapy
Didn’t reveal off treatment response of various combination
Didn’t compare combination therapy with monotherapy
27. ANSWERS STILL REQUIRED
How to diagnose antiviral resistance whether virological
breakthrough is sufficient or genetic study are required ??
How to monitor for AVR ??
How to manage patients with a suboptimal response to therapy or
the development of antiviral drug resistance ??.
28. Monitoring for Antiviral Resistance
Test serum HBV DNA prior to therapy and at 3 month intervals
Primary non-responders should be offered combination or
alternative therapy
Enquire about medication compliance when virologic breakthrough
is seen
Genotyping should be performed to confirm resistance and
determine specific mutations
Lok AS, et al. Hepatology. 2007;46:254-265.
29. Summary: AASLD Guidelines for Management of AntiviralResistant HBV
Resistance
Rescue Therapy
Lamivudine
Telbivudine
Add adefovir or tenofovir DF
Switch to:
Emtricitabine + tenofovir DF (fixed-dose combination)
Entecavir (risk of entecavir resistance)
Adefovir
Add lamivudine
Switch to:
Emtricitabine + tenofovir DF (fixed-dose combination)
Entecavir (if no prior lamivudine resistance)
Entecavir
Add adefovir or tenofovir DF
Multidrug
Multidrug resistance to lamivudine + adefovir:
Consider emtricitabine + tenofovir DF (fixed-dose combination),
tenofovir DF, entecavir
Multidrug resistance to lamivudine + entecavir:
Consider tenofovir DF or emtricitabine + tenofovir DF (fixed-dose
combination)
Lok AS, et al. Hepatology. 2007;46:254-265.
30. HBV genotypic resistance is common in HBV endemic area
Sequential therapy appears to raise the risk of
resistance, combinations of NA can be effective in
suppressing virus in these individuals
Combination of ADV/LAM is superior to ETV or ADV in
rescuing those with LAM resistance
Combination of LAM+ADV is superior to ETV montotherapy
for ADV-resistance
Addition of TDF to ETV gives the best response in those
K
with partial response to ETV monotherapy, and was superior
to ETV and TDF monotherapy
61st annual meeting of AASLD Hepatology 2010 Oct;52 Suppl:320A1291A.
31. DISCUSSION
Combination therapy with different cross-resistance
profiles were effective at achieving and maintaining CVS
for the majority of patients for either AVR or PR
Overall, the median time to achieve CVS was 6 months
Rapid and complete suppression of serum HBV DNA is an
important strategy to avoid the development of antiviral
drug resistance and treatment failure
In particular, serum HBV DNA should generally be
undetectable or <2000 IU/mL after 24 weeks of initial oral
therapy with a nucleos(t)ide agent
32. Summary
Combination therapy with 2 oral nucleos(t)ides is effective and
safe for patients with failure to earlier therapy.
No significant differences in the rate of CVS in patients with
either AVR or PR
No significant differences
whether TDF or ADV was used in combination with ETV
whether ETV or one of the weaker nucleosides
(LAM, LdT, FTC) was used in combination with TDF
33. Summary…..
Combination therapy with both of the 2 newer and more
expensive agents, ETV and TDF, may not be necessary when a
combination strategy is used.
Further studies are needed to help define the optimal selection
of agents to be used in combination therapy for CHB in the
setting of AVR or PR.
Notes de l'éditeur
4. There have been no studies addressing the issue ofwhether add-on (combination) therapy versus switchingto an alternative monotherapy is preferable in patientswith a suboptimal initial virological response to a singlenucleoside analog. Add-on therapy may be advisable if theinitial drug used has a low genetic barrier to resistance orif the duration of therapy has been prolonged becausethese factors increase the likelihood of drug-resistantHBV being present.
A related, but separate issue relates to the role of “addon” combination therapy in current treatment algorithms.For patients treated with nucleoside analogs, it isrecommended that antiviral response to treatment beevaluated at specific intervals and changes in therapymade in those with a “suboptimal” virological response.9,35 The guidelines indicate this change in drugtherapy can either be “add on” (i.e., adding the secondagent resulting in combination therapy) or a “switch”(i.e., switching to alternative single drug). There are norandomized studies that directly assess which strategy isbetter
defined as a documented rise in serum HBV DNA by >1 log10 IU/ mL from nadir during continuation of initial therapy
Ftc emtricitabine LdT telbivudine
Till recent little knowolefdge regarding combination